Abstract

Despite widespread use of the bacille Calmette–Guérin (BCG) vaccine, tuberculosis (TB) remains a leading cause of global mortality from a single infectious agent (Mycobacterium tuberculosis or Mtb). Here, over two independent Mtb challenge studies, we demonstrate that subcutaneous vaccination of rhesus macaques (RMs) with rhesus cytomegalovirus vectors encoding Mtb antigen inserts (hereafter referred to as RhCMV/TB)—which elicit and maintain highly effector-differentiated, circulating and tissue-resident Mtb-specific CD4+ and CD8+ memory T cell responses—can reduce the overall (pulmonary and extrapulmonary) extent of Mtb infection and disease by 68%, as compared to that in unvaccinated controls, after intrabronchial challenge with the Erdman strain of Mtb at 1 year after the first vaccination. Fourteen of 34 RhCMV/TB-vaccinated RMs (41%) across both studies showed no TB disease by computed tomography scans or at necropsy after challenge (as compared to 0 of 17 unvaccinated controls), and ten of these RMs were Mtb-culture-negative for all tissues, an exceptional long-term vaccine effect in the RM challenge model with the Erdman strain of Mtb. These results suggest that complete vaccine-mediated immune control of highly pathogenic Mtb is possible if immune effector responses can intercept Mtb infection at its earliest stages.

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Acknowledgements

We thank C. Kahl, S. Hagen, J. Bae, I. Pelletier, Y. Guo, E.M. Borst, L.S. Uebelhoer and J. Womack for technical assistance, C. Scanga and J. Flynn for guidance on the RM model of TB (including sharing of NHP protocols and provision of Mtb challenge stocks), P. Barry (University of California, Davis) and T. Shenk (Princeton University) for the 68-1 and 68-1.2 BACs, respectively, J. Flynn (University of Pittsburgh) for Mtb Erdman, W. Hanekom, L. Stuart and D. Barber for helpful discussions, D. Casimiro for manuscript review, J. Strussenberg for management of the BSL3 facility, L. Boshears for administrative assistance and A. Townsend for figure preparation. This work was supported by AERAS, the Bill and Melinda Gates Foundation (grant no. OPP1087783; A.A. and D.E.Z.) and the US National Institutes of Health (NIH; grant no. U19 AI106761 (A.A.), P51 OD011092 (ONPRC); U42 OD010426 (ONPRC)).

Author information

Author notes

    • Scott G Hansen
    • , Daniel E Zak
    •  & Guangwu Xu

    These authors contributed equally to this work.

Affiliations

  1. Vaccine and Gene Therapy Institute and Oregon National Primate Research Center (ONPRC), Oregon Health and Science University (OHSU), Beaverton, Oregon, USA.

    • Scott G Hansen
    • , Guangwu Xu
    • , Julia C Ford
    • , Emily E Marshall
    • , Daniel Malouli
    • , Roxanne M Gilbride
    • , Colette M Hughes
    • , Abigail B Ventura
    • , Emily Ainslie
    • , Kurt T Randall
    • , Andrea N Selseth
    • , Parker Rundstrom
    • , Lauren Herlache
    • , Matthew S Lewis
    • , Haesun Park
    • , Shannon L Planer
    • , John M Turner
    • , Miranda Fischer
    • , Christina Armstrong
    • , Robert C Zweig
    • , Andrew W Sylwester
    • , Alfred W Legasse
    • , Michael K Axthelm
    • , Klaus Früh
    •  & Louis J Picker
  2. Center for Infectious Disease Research, Seattle, Washington, USA.

    • Daniel E Zak
    • , Joseph Valvo
    • , Jackie M Braun
    • , Smitha Shankar
    • , Lynn M Amon
    •  & Alan Aderem
  3. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.

    • Lenette Lu
    •  & Galit Alter
  4. Department of Virology, Hannover Medical School, Hannover, Germany.

    • Martin Messerle
  5. School of Biomedical and Healthcare Sciences, University of Plymouth, Devon, UK.

    • Michael A Jarvis
  6. Aeras, Rockville, Maryland, USA.

    • Dominick J Laddy
    • , Michele Stone
    • , Aurelio Bonavia
    •  & Thomas G Evans
  7. Statistical Center for HIV–AIDS Research and Prevention, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Paul T Edlefsen

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Contributions

S.G.H. planned animal experiments and supervised all immunological and virological studies and data analysis; G.X. and J.C.F. processed monkey samples and tissues and performed immunological and bacteriological analyses, assisted by R.M.G., C.M.H., A.B.V., E.A., K.T.R., A.N.S., P.R., L.H., H.P. and M.S.L.; A.W.S. performed assay development and supervised flow cytometry; K.F., D.M., E.E.M., M.M. and M.A.J. designed, constructed and/or validated the RhCMV/TB vectors used in the study; A.W.L. supervised all animal procedures, including CT scanning, assisted by S.L.P., J.M.T., M.F., C.A., and R.C.Z.; M.K.A. planned and provided overall supervision of monkey protocols, interpreted CT scans, performed all necropsies and interpreted both gross pathology and histopathology; D.J.L. designed experimental approaches and reviewed data; M.S., A.B. and T.G.E. contributed to data interpretation and/or study design; L.L. performed the antibody assays under the supervision of G.A.; J.V., J.M.B. and S.S. processed samples and data for transcriptomic analysis; D.E.Z. planned, executed and interpreted the transcriptomics analysis, assisted by L.M.A., S.S., and A.A.; P.T.E. planned and performed all statistical analyses; L.J.P. conceived the RhCMV vector strategy, planned and supervised all experiments and data analysis, and wrote the manuscript, assisted by S.G.H., P.T.E., D.E.Z. and M.K.A.

Competing interests

OHSU, L.J.P., S.G.H., D.M. and K.F. have a significant financial interest in Vir Biotechnology, Inc., a company that may have a commercial interest in the results of this research and technology. The potential individual and institutional conflicts of interest have been reviewed and managed by OHSU. T.G.E. has served as a clinical consultant to Vir Biotechnology and also has a significant financial interest in that company.

Corresponding author

Correspondence to Louis J Picker.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–10

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    1482 Genes comparably regulated in TB patients and unvaccinated RM from Study 1 and Study 2 after Mtb challenge

  2. 2.

    Supplementary Table 2

    Pathway enrichments for genes comparably regulated in TB patients and unvaccinated RM from Study 1 and Study 2 after Mtb challenge

  3. 3.

    Supplementary Table 3

    214 genes with post-challenge expression patterns in vaccinated and unvaccinated RM that are highly significantly associated with scaled combined outcome measure

  4. 4.

    Supplementary Table 4

    Pathway enrichments for genes with post-challenge expression patterns that are highly significantly associated with scaled combined outcome measure

  5. 5.

    Supplementary Table 5

    258 genes with pre-challenge expression patterns in RhCMV-vaccinated RM that are significantly associated with scaled combined outcome measure

  6. 6.

    Supplementary Table 6

    Lists of genes exhibiting plausible associations with specific leukocyte populations for RhCMV/TB-vaccinated RM on the day of challenge

  7. 7.

    Supplementary Table 7

    Cell population enrichments for genes with pre-challenge expression patterns in RhCMV-vaccinated RM that are significantly associated with scaled combined outcome measure

  8. 8.

    Supplementary Table 8

    Pathway enrichments for genes with pre-challenge expression patterns in RhCMV-vaccinated RM that are significantly associated with scaled combined outcome measure

  9. 9.

    Supplementary Table 9

    Wilcoxon rank sum test statistics comparing expression levels of protection signature genes in the RhCMV/TB and BCG+RhCMV/TB groups from Study 1

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DOI

https://doi.org/10.1038/nm.4473

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